A CSF NPTX2-based residual metric captures prognostic heterogeneity within a proposed compensatory framework in prodromal Alzheimer’s disease

Background In Alzheimer’s disease(AD), core CSF biomarkers incompletely predict clinical progression. Synaptic biomarkers may add prognostic information by capturing distinct biological dimensions, from synaptic injury to adaptive network function. Although correlated, neurogranin (Ng) is interpreted as a marker of post-synaptic injury, whereas neuronal pentraxin-2(NPTX2) is more closely related to circuit homeostasis. We tested whether CSF NPTX2 contains a specific component statistically associated with a putative adaptive network signal, interpreted within a hypothesized compensatory framework, using clinical progression and brain metabolism as convergent readouts. Methods We retrospectively studied 104 patients with typical MCI-AD. CSF core AD biomarkers, NPTX2 and Ng were measured with commercial immunoassays. Early and late MCI stages were defined by proximity to dementia conversion (LMCI ≤ 2 years; EMCI > 2 years or stable). A residual NPTX2 measure(Res_NPTX2) was derived by regressing z-transformed NPTX2 on Ng, an index of AD burden based on tau/amyloid ratio, and age. Associations with MMSE and time-to-conversion were tested using linear and survival models. In all patients, brain [ 18 F]FDG PET was analyzed with voxel-based methods to identify metabolic correlates of NPTX2 and Res_NPTX2 relative to AD-related hypometabolic regions. Results Ng correlated strongly with NPTX2 (ρ = 0.67, p < 0.001). Res_NPTX2 was higher in EMCI than LMCI ( p = 0.0006), associated with better baseline MMSE ( p = 0.008), and predicted less MMSE decline over time ( p = 0.002). During follow-up, 55/104 patients(52.9%) progressed to dementia. Higher Res_NPTX2 predicted lower progression risk (HR = 0.63, p = 0.007), including after accounting for baseline MMSE. Kaplan–Meier curves differed across Res_NPTX2 tertiles, with the strongest separation within 2 years (high vs. low: HR = 0.18, p = 0.008). On [ 18 F]FDG PET, LMCI showed more marked left-sided posterior hypometabolism than EMCI. CSF NPTX2 and Res_NPTX2 were associated with distinct metabolic patterns centered on prominently left posterior parietal and right fronto-striatal regions, respectively. Conclusions In prodromal AD, CSF NPTX2 contains clinically relevant information beyond Ng and core biomarker burden. The proposed residualization approach provides a statistical strategy to isolate an NPTX2-related component associated with better cognition, lower short-term progression risk, and a precise right fronto-striatal metabolic signature. Within a hypothesized compensatory framework, this statistically isolated component may index a putative adaptive network capacity and help characterize clinically meaningful heterogeneity in early AD.